This invention relates to novel sulfonamide substituted diphenyl urea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 mediated diseases.
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2 or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROxcex1, GROxcex2, GROxcex3 and NAP-2 also belong to the chemokine family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAxcex1, xcex2 and xcex3 respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor (CXCR2).
IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146,427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL-8xcex2 receptor (CXCR2). Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rxcex1, which binds only IL-8 with high affinity, and IL-8Rxcex2, which has high affinity for IL-8 as well as for GROxcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds, which are capable of binding to the IL-8 xcex1 or xcex2 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein
Rb is independently selected from the group consisting of hydrogen, NR6R7, OH, ORa, C1-5alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl, cycloalkyl, cycloalkyl C1-5 alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, and a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono or di-C1-4 alkyl substituted amine, ORa,C(O)Ra,NRaC(O)ORa, OC(O)NR6R7, hydroxy, NR9C(O)Ra, S(O)mxe2x80x2Ra, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)2NR6R7 and NHS(O)2Ra; or the two Rb substituents join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 optionally substituted moieties selected from the group consisting of NRa, O, S, SO, and SO2; Ra is selected from the group consisting of alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COORa, and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted;
m is an integer having a value of 1 to 3;
mxe2x80x2 is 0, or an integer having a value of 1 or 2;
n is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10alkoxy, azide, S(O)tR4, (CR8R8)q S(O)tR4, hydroxy, hydroxy substituted C1-4alkyl, aryl, aryl C1-4 alkyl, aryl C2-10 alkenyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-10 alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclicC1-4alkyloxy, heterocyclicC2-10 alkenyl, (CR8R8)q NR4R5, (CR8R8)qC(O)NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R10, S(O)3R8, (CR8R8)q C(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)q C(O)OR11, (CR8R8)q OC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)q C(NR4)NR4R5, (CR8R8)q NR4C(NR5)R11, (CR8R8)q NHS(O)2R13, and (CR8R8)q S(O)2NR4R5; or two R1 moieties together may form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring, such that the alkyl, aryl, arylalkyl, heteroaryl, or heterocyclic moieties may be optionally substituted;
R4 and R5 are independently selected form the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, and heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S;
R6 and R7 are independently selected from the group consisting of hydrogen, a C1-4 alkyl, heteroaryl, aryl, aklyl aryl, and alkyl C1-4 heteroalkyl; or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which is selected from the group consisting of oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
Y is selected from the group consisting of furan, thiophene, pyrrole, oxazole, imidazole, thiazole, pyrazole, isooxazole, isothiazole, 1,2,3 or 1,2,4 oxadiazole, 1,2,3 or 1,2,4 triazole, 1,2,3 or 1,2,4 thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5, or 1,2,3 or 1,2,4 triazine, 1,2,4,5 tetrazine, indole, benzofuran, indazole, benzimidazole, benzothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline all of which moeities can be substituted 1-3 times with R1 
R8 is hydrogen or C1-4 alkyl;
R9 is hydrogen or a C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl; and
R13 is selected from the group consisting of C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula (I), may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 xcex1 and xcex2 receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
Suitably, Rb is independently hydrogen, NR6R7, OH, ORa, C1-4alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono or di-C1-4 alkyl substituted amine, cycloalkyl, cycloalkyl C1-5 alkyl, ORa, C(O)Ra, NRaC(O)ORa, OC(O)NR6R7, aryloxy, aryl C1-4 oxy, hydroxy, C1-4 alkoxy, NR9C(O)Ra, S(O)mxe2x80x2Ra, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)2NR6R7, NHS(O)2Ra. Alternatively, the two Rb substituents can join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 NR9, O, S, SO, or SO2 moities which can be optionally substituted.
Suitably, Ra is an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted.
Suitably, R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl, such as CF3, C1-10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl, C2-10 alkenyl, C1-10 alkoxy, such as methoxy, or ethoxy; halosubstituted C1-10 alkoxy, such as trifluoromethoxy, azide, (CR8R8)q S(O)tR4, wherein t is 0, 1 or 2, hydroxy, hydroxy C1-4alkyl, such as methanol or ethanol, aryl, such as phenyl or naphthyl, aryl C1-4 alkyl, such as benzyl, aryloxy, such as phenoxy, aryl C1-4 alkyloxy, such as benzyloxy; heteroaryl, heteroarylalkyl, heteroaryl C1-4 alyloxy; aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3H, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)q C(O)R11, (CR8R8)qC(O)OR11, (CR8R8)q OC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)q NR4C(NR5)R11, (CR8R8)qNHS(O)2R13, (CR8R8)qS(O)2NR4R5. All of the aryl, heteroaryl, and heterocyclic-containing moieties may be optionally substituted as defined herein below.
For use herein the term xe2x80x9cthe aryl, heteroaryl, and heterocyclic containing moietiesxe2x80x9d refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term xe2x80x9cmoietiesxe2x80x9d and xe2x80x9cringsxe2x80x9d may be interchangeably used throughout.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 allyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S.
Suitably, R8 is independently hydrogen or C1-4 alkyl.
Suitably, R9 is hydrogen or a C1-4 alkyl;
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, R10 is C1-10 alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
Suitably, R11 is hydrogen, C1-4 alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4alyl, heterocyclic, or heterocyclic C1-4alkyl.
Suitably, R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.
Suitably, R13 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
Suitably, Y is is furan, thiophene, pyrrole, oxazole, imidazole, thiazole, pyrazole, isooxazole, isothiazole, 1,2,3 or 1,2,4 oxadiazole, 1,2,3 or 1,2,4 triazole, 1,2,3 or 1,2,4 thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5, or 1,2,3 or 1,2,4 triazine, 1,2,4,5 tetrazine, indole, benzofuran, indazole, benzimidazole, benzothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline all of which moeities can be substituted 1-3 times with R1; C2-10 alkenyl C(O)OR11; (CR8R8)q C(O)OR12; (CR8R8)q OC(O) R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)q NR4C(NR5)R11; (CR8R8)q NR4C(O)R11; (CR8R8)q NHS(O)2R13; or (CR8R8)q S(O)2NR4R5; or two Y moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
Suitably s is an integer having a value of 1 to 3.
Suitably, Ra is an alkyl, aryl C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclic, or a heterocyclicC1-4 alkyl, wherein all of these moieties may all be optionally substituted.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine, hydroxy; hydroxy substituted C1-10alkyl, C1-10 alkoxy, such as methoxy or ethoxy, S(O)mxe2x80x2C1-10 alkyl, wherein mxe2x80x2 is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR4R5 group, NHC(O)R4, C(O)NR4R5, C(O)OH, S(O)2NR4R5, NHS(O)2R20, C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl, halosubstituted C1-10 alkyl, such CF3, an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclically, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl, heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl, C1-10 alkoxy; S(O)mxe2x80x2C1-10 alkyl; amino, mono and di-substituted alkyl amino, such as in the NR4R5 group; C1-10 alkyl, or halosubstituted C1-10 alkyl, such as CF3.
R20 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclicalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfur may be optionally oxidized to the sulfone or the sulfoxide.
xe2x80x9carylalkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S (O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
xe2x80x9cwherein two R1 moieties may together form a 5 or 6 membered saturated or unsaturated ringxe2x80x9d is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Illustrative compounds of Formula (I) include:
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(pyridin-2-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(2-chloro-pyridin-3-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(1-phenyl-1H-1,2,3-triazol-5-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(1,3-dimethylpyrazol-5-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(1-methylpyrazol-5-yl)urea; and
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(2-methyl-pyridin-3-yl)urea.
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(3,5-dimethylisoxazol-4-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(1-N-oxide-pyridin-3-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(2-choro-1-N-oxide-pyridin-3-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(3-benzyloxythieno[2,3-b]pyridin-2-yl)urea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(3-methylisoxazol-4-yl)urea; and
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(5-methylisoxazol-4-yl)urea.
The compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the producing compounds of Formulas (I) having a variety of different R, R1, and Z groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. 
The route to the 2,4 dichloro sulfonamide 5-scheme 1 is outlined above, wherein the commercially available 2,6-dichloro thiol can be oxidized to the sulfonyl halide using a halogenating agent such as NCS, NBS, chlorine or bromine in the presence of a protic solvent such as alcohol, acetic acid or water. The sulfonyl halide can be hydrolyzed by using a metal hydroxide such as sodium or potassium hydroxide to form the corresponding sulfonic acid salt. The sulfonic acid salt can then be nitrated under nitration conditions such as nitric acid in a solvent of strong acid such as sulfuric acid to form the nitro phenyl sulfonic acid 3-scheme 1. The sulfonic acid 3-scheme 1 can be converted to the sulfonamide 5-scheme 1 using a three step procedure involving the formation of the metal salt using a base such as sodium hydroxide, sodium hydride or sodium carbonate to form 4-scheme 1. The sulfonic acid salt is then converted to the sulfonyl chloride using PCl5 with POCl3 as a solvent. The sulfonyl chloride can then be converted to the corresponding sulfonamide using the desired amine HNRxe2x80x2Rxe2x80x3 in a non-protic solvent such as CH2Cl2 using a base such as triethyl amine at temperatures ranging from xe2x88x9278xc2x0 C. to 60xc2x0 C. to form the corresponding sulfonamide 5-scheme 3. This method is not limited to the 2,6-dichlorophenyl thiol it can also be applied to the 2,6-difluorophenyl thiol, 2,6-dibromophenyl thiol and the 2,6-diiodophenyl thiol. The halogens in these compounds can be converted to the corresponding cyano, amino, thiol, or alkoxy compounds by nucleophilic displacement reactions using nucleophiles such as alkyl thiolates, alkoxides, amine and cyanides. The halogens can also be further functionalized by palladium coupling and carbonylation reactions, well known in the art, to form the corresponding amido, carbonyl, alkenyl, alkyl, phenyl and heterocycic substituted products as required by Formula (I).
The ortho chloride can be selectively hydrolyzed by using a hydroxide base in a protic or non protic solvent or by in situ generation of hydroxide by the use of NaH and water in a non protic solvent such as THF to form 2-scheme 2. The nitro can then be reduced using a number of reduced agents such as palladium on carbon and hydrogen, tin chloride, iron, rhodium or sodium sulfite to form the desired aniline 3-scheme 2. 
If the desired hydroxyaniline 3 in Scheme 2 is not commercially available, it can be prepared as outlined in Scheme 3. Commercially available substituted 3-chloroanilines 1 can be converted to the amide 2 using standard conditions well known in the art such as pivavolyl chloride and triethylamine in a suitable organic solvent such as methylene chloride. The amide 2 can be converted to the benzoxazole 3 using an excess amount of a strong base such as butyllithium in a suitable organic solvent such as THF under reduced reaction temperatures (xe2x88x9220 to xe2x88x9240xc2x0 C.) followed by quenching the reaction with sulfur dioxide gas. The sulfonic acid 3 can be converted to the sulfonamide 4 using via the intermediate sulfurylchloride. The sulfonyl chloride can be obtained from the sulfonic acid 3 using standard conditions well known in the art such as sulfuryl chloride in a suitable organic solvent such as methylene chloride. The sulfonyl chloride intermediate can be transformed to the sulfonamide 4 using standard conditons well known in the art by reacting it with the amine HN(Rb)2 in the presence of a suitable amine base such as triethylamine in a suitable organic solvent such as methylene chloride. The desired phenolaniline 5 can be obtained from the benzoxazole 4 using standard hydrolysis conditions well known in the art such as sulfuric acid in water and heating at 85xc2x0 C. 
The urea can be formed by coupling the heterocyclic isocyanate with desired hydroxyaniline. If the desired heterocyclic isocyanate is unstable like the 2-pyridyl isocyanate, the isocyanate is generated in the presence of hydroaniline by premixing the acylazide with hydroxy aniline and trapping the heterocyclic isocyanate in situ. The acyl azide can be generated by treating the carboxy heterocycle with D)PPA or by a two step procedure involving formation of the acid halide or mixed anhydride followed by attack with an azide salt such as sodium azide. If the isocyanate is stable then the isocyanate can be formed by reaction of the corresponding heterocyclic amine with triphosgene. 
Alternatively the isocyanate can be formed on the other side of the urea by first protecting the hydroxyl using a standard protecting group such as TBS to form 2 scheme 5. The protected hydroxy aniline is then converted to the isocyanate using standard conditions such as treatment with triphosgene in the presence of a base such as triethyl amine or sodium bicarbonate to form 3 scheme 5. The isocyanate is then coupled with heterocyclic amine to form the corresponding urea followed by deprotection of the phenol group using standard procedures to form the desired compound 4 scheme 5. 
The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated.
In the Examples, all temperatures are in degrees Centigrade (xc2x0 C.). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. 1H-NMR (hereinafter xe2x80x9cNMRxe2x80x9d) spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
General Method
Synthesis of 3-(aminosulfonyl)-4-chloro-2-hydroxy aniline.
a) 2,6-Dichlorobenzenesulfonyl chloride
Into a mixture of 200 milliliters (hereinafter xe2x80x9cmLxe2x80x9d) of acetic acid, water and dichloromethane (3/1/4, v/v/v), 2,6-dichlorobenzenethiol (10.0 grams (hereinafter xe2x80x9cgxe2x80x9d), 55.8 millimoles (hereinafter xe2x80x9cmmolxe2x80x9d), N-chlorosuccinimide (37.28 g, 279 mmol) and potassium acetate (2.29 g, 27.9 mmol) were added. The resulting mixture was stirred at 0xc2x0 C., then warmed to room temperature overnight. The mixture was then diluted with 200 mL of dichloromethane, and washed with water (100 mLxc3x973). The organic layer was dried (Na2SO4) and concentrated to give the desired product (11 g, 80%). 1H NMR (CDCl3): xcex47.57 (d, 2H), 7.47 (t, 1H).2,6-Dichloro-3-nitrobenzenesulfonic acid. Lithium hydroxide hydrate (12.64 g, 0.301 mol) was added to a solution of 2,6-dichlorobenzenesulfonyl chloride (35.53 g, 0.146 mol) in MeOH (600 mL) and the reaction was allowed to stir at room temperature for 3 hr. The reaction mixture was filtered to remove suspended solids and then concentrated. The resulting solid was dried in vacu overnight to remove any residual MeOH. The solid was then dissolved in H2SO4 (300 mL) and chilled in an ice bath. A solution of H2SO4 (35 mL) and HNO3 (13.2 mL) was slowly added to the above reaction over 90 min. The reaction was allowed to warm up to room temperature overnight and then slowly poured into ice water (1200 mL) and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated to yield 2,6-dichloro-3-nitrobenzenesulfonic acid (44.35 g, 99%) as the dihydrate. EI-MS (m/z) 270 (Mxe2x88x92H)xe2x88x92.
b) 2,6-Dichloro-3-nitrobenzenesulfonyl chloride
Potassium hydroxide (12.07 g, 0.215 mol) was added to a solution of 2,6-dichloro-3-nitrobenzenesulfonic acid dihydrate (44.35 g, 0.144 mol) in MeOH (850 mL) and the reaction was allowed to stir at room temperature for 14 hr. The reaction mixture was concentrated and the resulting solid was dried in vacu overnight. To this was added PCl5 (30.00 g, 0.144 mol) followed by POCl3 (475 mL) and the mixture was refluxed overnight. The reaction was then cooled to room temperature and concentrated. The resulting mixture was taken up in EtOAc and chilled in an ice bath. Ice chunks were slowly added to the reaction mixture to quench any leftover PCl5. When bubbling ceased, water was added and the reaction mix was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to yield 2,6-Dichloro-3-nitrobenzenesulfonyl chloride (40.42 g, 97%). 1H NMR (DMSO-d6); 7.88 (d, 1H), 7.75 (d, 1H).
c) 2,6-dichloro-3-nitrobenzenesulfonamide
Into a solution of 2,6-dichloro-3-nitrobenzenesulfonyl chloride (9.48 g, 32.6 mmol) in 105 mL of dichloromethane at xe2x88x9278xc2x0 C. was bulbed amonia gas for 6 hours. The mixture was warmed to room temperature and acidified to pH greater than 1 with 6N aq. HCl, then extracted with ethyl acetate. The combined organic layer was then concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane (50/50, v/v/), gave the desired product (6.30 g, 71%). 1H NMR (DMSO-d6): xcex48.26 (s, 2H), 8.20 (d, 1H), 7.92 (d, 1H).
d) 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide
A mixture of 2,6-dichloro-3-nitrobenzenesulfonamide (2.61 g, 9.64 mmol), 60% sodium hydride (1.15 g, 28.9 mmol) and water (174 xcexcL, 9.64 mmol) was heated to 45xc2x0 C. while kept at argon atmosphere for 3 days. The reaction was monitored by 1H NMR. 0.1 equivalent water was added to the mixture when the reaction was not completed. The solvent was evaporated when the reaction almost completed indicated by 1H NMR. The residue was diluted with ethyl acetate and washed with 1N aq. HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/48/2, v/v/v), gave the desired product (1.87 g, 77%). EI-MS (m/z)250.84, 252.89 (Mxe2x88x92).
e) 3-amino-6-chloro-2-hydroxybenzenesulfonamide
To a solution of 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (3 g, 11.9 mmol) in ethyl acetate, was added 10% Pd/C (1.24 g). The mixture was flushed with argon, and then stirred on Parr apparatus at 40 psi for 25 min at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (2.51 g, 95%). EI-MS (m/z) 222.75, 224.74 (Mxe2x88x92).
f) N-(3,4-Dichloro-phenyl)-2,2-dimethyl-propionamide
3,4-dichloroaniline (150 g) in TBME (1L) was cooled to 10-15xc2x0 C. 30% aq NaOH (141 g, 1.14 equiv) was added, and the solution stirred vigorously via overhead mechanical stirrer. Trimethylacetyl chloride (xe2x80x9cPivClxe2x80x9d, 126 mL) was added at such a rate as to keep the internal temperature below 30xc2x0 C. During this addition, the solution mixture becomes thick with white solid product. When the addition was complete (10-15 min), the mixture was heated to 30-35xc2x0 C. for 1 hr, and then allowed to cool. The reaction mixture was held at xe2x88x925xc2x0 C. (overnight), and then filtered, rinsing first with 90:10 water/MeOH (600 mL) and then water (900 mL). Drying under vacuum yielded 195 g (86%) product, as off-white crystals. LCMS m/z 246(Mxe2x88x92H)+.
g) 2-tert-Butyl-6-chloro-benzooxazole-7-sulfonyl chloride
The solution of N-(3,4-dichloro-phenyl)-2,2-dimethyl-propionamide (10 g, 41 mmol) in dry THF (100 mL) was cooled to xe2x88x9272xc2x0 C. under argon. n-Butyl lithium (1.6M in hexane, 64 mL, 102 mmol) was added dropwise. The solution warmed to ca. xe2x88x9250xc2x0 C. over 45 minutes, and then was kept in the xe2x88x9225-xe2x88x9210xc2x0 C. range for 2 hrs. The solution was then recooled to xe2x88x9278xc2x0 C., and sulfur dioxide was bubbled through the solution for 30 min. The solution was then allowed to warm to room temperature for 2 h, and a Ar stream was bubbled through the solution, with a gas outlet provided so that any excess sulfur dioxide could escape during the warming. The THF solution was cooled in an ice bath, and sulfuryl chloride (3.58 mL, 44.9 mmol) was added dropwise. After a few minutes, the solution was warmed to room temperature for overnight. The mixture was concentrated, diluted with ethyl acetate and washed with water. Decolorizing carbon was added and the mixture was filtered. The resulting solution was dried (sodium sulfate), filtered and concentrated to afford the title compound (12.4 g, 98%). 1H NMR (CDCl3).7.92 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.4 Hz), 1.57 (s, 9H). General procedure for the hydrolysis of the benzooxazole to the desired aniline.
To a solution of 2-tert-Butyl-6-chloro-7-(aminosulfonyl)-benzooxazole in 1,4-dioxane (20 mL) was treated with water (4 mL) and conc. H2SO4 (4 mL). The mixture was heated to 85xc2x0 C. for 14 h. The reaction was cooled to room temperature, and then basified to pH=14 with 25% aq NaOH. washed. The mixture was extracted with ethyl acetate (3 times), dried with MgSO4, filtered, and concentrated to afford the title compound.